Methods For Monitoring Transdermal Drug Delivery Analytical/Radio/Nuclear (ARN) Seminar Jivan Yewle Department of Chemistry University of Kentucky

Overview  Introduction  Skin Physiology  Transdermal Drug Delivery (TDD)  Methods For Monitoring TDD  Confocal Laser scanning microscopy (CLSM)  Two photon fluorescence microscopy (TPFM)  Infrared Microscopic Imaging  Raman Microscopic Imaging  Instrumentation  Applications  Advantages and Limitations

Introduction Types of Drug Delivery system  Oral Drug Delivery  Intravascular Drug Delivery  Transmucosal Drug Delivery  Transdermal Drug Delivery (TDD)

Skin Physiology Epidermis Dermis Subcutaneous tissue Stratum corneum

Skin Physiology Characteristics:  Tough  Flexible  Poor conductor of electricity Functions of skin:  To protect the body from external insults  To contain all body fluids  To regulate body temperature  To protect from electrical current

Transdermal Drug Delivery  Delivery of drug through skin  Drugs (birth control patches, nicotine patches)  Transdermal patches

Transdermal Drug Delivery Mechanism  Penetration  Intercellular route  Follicular route  Diffusion

Transdermal Drug Delivery Advantages of TDD:  Steady permeation of drug across skin  Controlled drug delivery  Good for acid and enzyme reactive drugs.  Minimum risk of side effects  Limited toxic effects (if)  Convenience : may require only once weekly  Easy drug administration  Good for lipophilic drug molecules

Transdermal Drug Delivery Disadvantages and limitations of TDD  Possibility of a local irritation  Allergic reactions are possible  Risky for children  Skin's low permeability  Molecular size and polarity of drug  Insufficient bioavailability  Damage to a transdermal patch

Transdermal Drug Delivery Strategies for improving transport rate Penetration enhancers ( eg: Water, Terpenes, Oleic acids, Menthol, Azones )  Reduces barrier function of skin  Some penetration enhancers remove lipids from the skin  Water: a natural penetration enhancer  Alcohol: a solvent as well as a penetration enhancer

Transdermal Drug Delivery Strategies for improving transport rate Liposomes (Lipid vesicles)  Spherical vesicles with a membrane composed of a phosholipid bilayer  Created by sonicating phospholipids in water  Encapsulates drug molecule  Lipid bilayer can fuse with other bilayers  It neither penetrates nor fuses to SC  It can be sensitive to temp, pH, light etc.

Instrumental tools for monitoring TDD 1.Confocal Laser scanning microscopy (CLSM) 2.Two photon fluorescence microscopy (TPFM) 3.Infrared Microscopic Imaging 4.Raman Microscopic Imaging

1. Confocal Laser scanning microscopy Instrumentation

1. Confocal Laser scanning microscopy Applications in TDD  Images parallel to skin surface  Position of drug molecule under skin surface  Information about penetration of drug Other applications  Evaluation of biological phenomenon  Transport studies through biological membrane  Surface study of different material

1. Confocal Laser scanning microscopy Advantages  Images of thick specimens at various depth  3D confocal images  High degree of precision  Blur-free images Limitations and disadvantages  Information about permeation of fluorescent label only  Images up to 25 m depth only  Smaller signal to noise ratio

2.Two Photon fluorescence microscopy Instrumentation

2.Two Photon fluorescence microscopy Applications in TDD  Deeper images of skin up to 1mm  Position of drug molecule under skin surface  Information about penetration of drug

2.Two Photon fluorescence microscopy Advantages  Imaging up to depth of 1mm  Deeper tissue penetration  Reduced phototoxicity  Use of infrared light to excite fluorophores  High-resolution imaging. Limitations  Substance to be studied should have fluorophores

Methods For Monitoring TDD 3. Infrared Microscopic Imaging Instrumentation

3. Infrared Microscopic Imaging Application in TDD 1,2-dipalmitoylphosphatidylcholine (DPPC-d 62 ) C. Xiao, C.R. Flach, R. Mendelsohn. J Invest Dermatol. (2005), 124, CD2-Symm/asymm-2100/2200 Amide-1650/1550 CH2-stre

3. Infrared Microscopic Imaging Advantages  Sampling of much greater area (few mm)  Higher signal to noise ratio Limitations  Unsuited to cofocal application  Limited applications for in vivo potential  Low spatial resolution (10-12 m)  Requires careful sectioning of the skin (5 m)

Methods For Monitoring TDD 4. Raman Microscopic Imaging Application in TDD CD2 Stretching cm-1 C. Xiao, C.R. Flach, R. Mendelsohn. J Invest Dermatol. (2005), 124,

4. Raman Microscopic Imaging Advantages  Non-intrusive and non-destructive  Analysis at various temperatures  Analysis within sealed systems  Direct spatially resolved concentration  Molecular structure information  Higher spatial resolution (1-2 m)

4. Raman Microscopic Imaging Applications  Surface and materials science  Forensic research / investigation  Polymer science  Geology  Pharmaceutical science Limitations  Possibility of errors

Summary  Transdermal drug delivery is an effective technique for steady and consistent drug delivery.  Penetration enhancers and liposomes are good solutions for the slow permeation of the skin.  IR and Raman Microscopic imaging techniques are more useful than others to monitor TDD.

References 1.I.V. Zhigaltesv, N. Maurer. Biochemicaet Biophysica Acta. (2002), 1565, C. Xiao, C.R. Flach, R. Mendelsohn. J Invest Dermatol. (2005), 124, K.M.Hanson, R.M.Clegg. Biophys J. (2002), 83, 1682– E.N.Lewis,P.J.Treado. Anal Chem. (1995), 67, 3377– C.Xiao, R.Mendelsohn. Appl Spectrosc. (2004), 58, 382– P.J.Caspers, G.J.Puppels. Biospectroscopy (1998), 4, S31–S

Acknowledgements Dr. Vasilios Gavalas University of Kentucky Chemistry Department